The present invention relates to substituted diphenyl heterocycles and compositions thereof useful for treating or preventing Hepatitis C virus (HCV) infections. In particular, the present invention relates to substituted diphenyl isoxazole, pyrazole and oxadiazole compounds, compositions comprising the compounds and the use of such compounds and compositions to inhibit HCV replication and/or proliferation as a therapeutic approach towards the treatment and/or prevention of HCV infections in humans and animals.
Hepatitis C virus (HCV) infection is a global human health problem with approximately 150,000 new reported cases each year in the United States alone. HCV is a single stranded RNA virus, which is the etiological agent identified in most cases of non-A, non-B post-transfusion and post-transplant hepatitis and is a common cause of acute sporadic hepatitis (Choo et al., Science 244:359, 1989; Kuo et al., Science 244:362, 1989; and Alter et al., in Current Perspective in Hepatology, p. 83, 1989). It is estimated that more than 50% of patients infected with HCV become chronically infected and 20% of those develop cirrhosis of the liver within 20 years (Davis et al., New Engl. J. Med. 321:1501, 1989; Alter et al., in Current Perspective in Hepatology, p. 83, 1989; Alter et al., New Engl. J. Med. 327:1899, 1992; and Dienstag Gastroenterology 85:430, 1983). Moreover, the only therapy available for treatment of HCV infection is interferon-xcex1 (INTRON(copyright) A, PEG-INTRON(copyright) A, Schering-Plough; ROFERON-A(copyright), PEGASys(copyright), Roche). Most patients are unresponsive, however, and among the responders, there is a high recurrence rate within 6-12 months after cessation of treatment (Liang et al., J. Med. Virol. 40:69, 1993). Ribavirin, a guanosine analog with broad spectrum activity against many RNA and DNA viruses, has been shown in clinical trials to be effective against chronic HCV infection when used in combination with interferon-xcex1 (see, e.g., Poynard et al., Lancet 352:1426-1432, 1998; Reichard et al., Lancet 351:83-87, 1998), and this combination therapy has been recently approved (REBETRON, Schering-Plough; see also Fried et al., 2002, N. Engl. J. Med. 347:975-982). However, the response rate is still at or below 50%. Therefore, additional compounds for treatment and prevention of HCV infection are needed.
In one aspect, the present invention provides substituted diphenyl heterocycles that are potent inhibitors of Hepatitis C virus (xe2x80x9cHCVxe2x80x9d) replication and/or proliferation. In one embodiment, the compounds are substituted diphenyl isoxazole, pyrazole and/or oxadiazole compounds according to structural formula (I): 
where Z is CH (isoxazoles, or pyrazoles) or N (oxadiazoles) and X and Y are each, independently of one another, O and N, provided that: (i) X and Y are not both O and (ii) when X and Y are each N, then Z is CH. The xe2x80x9cAxe2x80x9d phenyl ring includes at least one, and in many instances two, substituents positioned ortho to the point of attachment (R2 and/or R6) and optionally from 1 to 4 additional substituents, which may be the same or different. Although the xe2x80x9cAxe2x80x9d ring may include a single ortho (R2 or R6) substituent, compounds which include two ortho substituents (R2 and R6) are particularly active and useful. It is preferable that at least one of the substituent groups at positions R2 and/or R6 provide some steric bulk. For example, it is preferable that the R2 and/or R6 substituent be larger than a fluoro group.
The nature of the R2 and/or R6 substituents, as well as the optional substituents at positions R3, R4 and R5, can vary widely. As a consequence, the xe2x80x9cAxe2x80x9d phenyl ring may be substituted with virtually any substituent groups, provided that at least one of R2 or R6 is other than hydrogen. When the xe2x80x9cAxe2x80x9d phenyl ring includes more than one substituent, the substituents may be the same or different. Typical substituent groups useful for substituting the xe2x80x9cAxe2x80x9d ring include, but are not limited to, branched, straight-chain or cyclic alkyls, mono- or polycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos, branched, straight-chain or cyclic haloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys, branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos, azides, amines (primary, secondary and tertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic esters, etc., and combinations of these groups.
These substituent groups may be further substituted at one or more available carbon or heteroatoms with the same or different additional substituents, which may be selected from the substituents described above. Any reactive functionalities in the groups used to substituted the xe2x80x9cAxe2x80x9d phenyl ring may be masked with a protecting group or a progroup, as is well-known in the art.
The substituent groups may be attached directly to the phenyl ring, or they may be spaced away from the ring by way of a linker. The nature of the linker can vary widely, and can include virtually any combination of atoms or groups useful for spacing one molecular moiety from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like), a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94PHxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)NHxe2x80x94, xe2x80x94S(O)2NHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino, thiopheno, piperidino, piperazino, pyrizidino, pyrrolidino, and the like) or combinations of such bridges. In one embodiment, the xe2x80x9cAxe2x80x9d ring is substituted at both R2 and R6 with the same or different halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, methoxy, haloalkyl, trifluoromethyl, 5-6 membered cycloheteroalkyl or substituted 5-6 membered cycloheteroalkyl group.
The xe2x80x9cCxe2x80x9d ring is substituted at the meta position with a group of the formula xe2x80x94NR11C(O)R12, where R11 is hydrogen or lower alkyl and R12 is monohalomethyl or dihalomethyl. The xe2x80x9cCxe2x80x9d ring may optionally include from 1 to 4 additional substituents (R8, R9, R10 and/or R13), which may be the same or different. As for the xe2x80x9cAxe2x80x9d phenyl ring, the nature of the optional R8, R9, R10 and R13 substituents can vary broadly. Groups useful for substituting the xe2x80x9cCxe2x80x9d phenyl ring are the same as those described for the xe2x80x9cAxe2x80x9d phenyl ring, supra. In one embodiment, the xe2x80x9cCxe2x80x9d ring does not include optional substituents, such that R8, R9, R10 and R13 are each hydrogen.
As will be recognized by skilled artisans, the actual electron distribution or double bonding pattern of the xe2x80x9cBxe2x80x9d ring will depend upon the identities of substituents X and Y. As illustrated, structural formula (I) is specifically intended to include at least the following six structures: 
In another aspect, the invention provides starting and intermediate compounds useful for synthesizing the compounds of the invention. Representative starting and intermediate compounds useful for synthesizing isoxazole and pyrazole compounds of the invention include compounds 201, 203, 205, 207, 209, 223, 225, 227, 229, 231, 245, 247, 248a, 248b, 249, 257 and 259 as depicted in FIGS. 1-7. Representative starting and intermediate compounds useful for synthesizing oxadiazole compounds of the invention include compounds 265, 267, 269, 271, 285, 287 and 289 as depicted in FIGS. 1-7.
In one embodiment, the intermediates are compounds according to structural formula (II): 
wherein R15 is NO2 or NHR, where R is hydrogen, lower alkyl or a protecting group and X, Y, Z, R2, R3, R4, R5, R6, R8, R9, R10 and R13 are as previously defined for structural formula (I) and subject to the same provisos. Like the compounds of structural formula (I), in the compounds of structural formula (II) the double bonding pattern will depend upon the identities of substituents X and Y.
In another aspect, the invention provides methods of making the substituted diphenyl heterocycle compounds of structural formula (I) or (II). Specific exemplary embodiments of the methods are illustrated in FIGS. 1-7. In one embodiment, the method for synthesizing compounds according to structural formula (I) comprises optionally alkylating a compound according to structural formula (II) in which R15 is NHR with an alkylating agent (e.g., R11-halide) followed by optional deprotection and acylation with an acylating agent of the formula LGxe2x80x94C(O)xe2x80x94R12, where xe2x80x9cLGxe2x80x9d represents a leaving group or an activating group and R12 is as previously defined in connection with the compounds of formula (I).
In another aspect, the present invention provides compositions comprising the compounds of the invention. The compositions generally comprise a substituted diphenyl isoxazole, pyrazole or oxadiazole of the invention, or a salt, hydrate, solvate, N-oxide or prodrug thereof and a suitable excipient, carrier or diluent. The composition may be formulated for veterinary uses or for use in humans.
The compounds of the invention are potent inhibitors of HCV replication and/or proliferation. Accordingly, in still another aspect, the present invention provides methods of inhibiting HCV replication and/or proliferation, comprising contacting a Hepatitis C virion with an amount of a compound or composition of the invention effective to inhibit its replication or proliferation. The methods may be practiced either in vitro or in vivo, and may be used as a therapeutic approach towards the treatment and/or prevention of HCV infections.
In a final aspect, the present invention provides methods of treating and/or preventing HCV infections. The methods generally involve administering to a subject that has an HCV infection or that is at risk of developing an HCV infection an amount of a compound or composition of the invention effective to treat or prevent the HCV infection. The method may be practiced in animals in veterinary contexts or in humans.